M TUBERCULOSIS ADENOSINE KINASE AND ANTI-MICROBIAL NUCLEOSIDE ANALOGS

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 结核分枝杆菌是一种机会性感染病原体，在世界范围内引起结核病和发病率和死亡率。多药耐药（MDR）菌株的出现和艾滋病相关的结核病感染导致迫切需要开发用于结核病治疗的新的和有效的治疗剂。腺苷激酶来自M.结核分枝杆菌（Mtb-AK）最近被鉴定为负责一组核苷类似物抗结核分枝杆菌的生物活化。结核我们的长期目标是开发新的抗分枝杆菌药物，利用特异性激活的核苷前体药物的Mtb-AK，嘌呤补救途径中的关键酶。我们的具体目标是：1）。研究不同形态的Mtb-AK的晶体结构，探讨腺苷磷酸化和腺苷类似物在M.结核 2)表征酶的底物偏好的结构基础和可以被Mtb-AK更有效和选择性地激活的核苷类似物的结构特征。 3)研究腺苷类似物与Mtb-AK复合物的结构，为核苷类似物的优化提供结构基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mycobacterium tuberculosis is an opportunistic infection pathogen that causes TB and morbidity and mortality worldwide. The emergence of multi-drug resistance (MDR) strains and the AIDS-associated TB infection has led to a critical need for the development of new and effective therapeutic agents for the TB treatment. Adenosine kinase from M. tuberculosis (Mtb-AK) has recently been identified to be responsible for the bioactivation of a group of nucleoside analogs against M. tuberculosis. Our long-term goal is to develop new antimycobacterial agents by exploiting the specific activation of a nucleoside prodrug by Mtb-AK, a key enzyme in the purine salvage pathway. Our specific aims are: 1). to characterize the crystal structure of Mtb-AK in different forms and to elute the enzyme reaction mechanism involved in adenosine phosphorylation and bioactivation of adenosine analogs in M. tuberculosis. 2) To characterize the structural basis of the enzyme's substrate preferences and the structural features of nucleoside analogs that can be activated more efficiently and selectively by Mtb-AK. 3) To characterize the Mtb-AK complex structures with the lead adenosine analogs and the structural basis for optimization of nucleoside analogs.